This invention relates to novel cyanoguanidine derivatives useful as therapeutic agents for circulation system disorders such as hypertension, angina pectoris and the like.
It is known that there are several ion channels in the cell membranes of smooth muscle such as vascular smooth muscle. These channels include sodium ion (Na.sup.+) channels, potassium ion (K.sup.+) channels, calcium ion (Ca.sup.++) channels etc. which selectively regulate the permeability to their respective ions in the cell. These channels function to regulate the contraction and relaxation of the smooth muscle by opening or closing the channels in response to the modulation of receptors or potentials on the cell membranes. When K.sup.+ channels are opened, the increased permeability of the cell membrane allows more potassium ions to migrate outwardly so that the membrane potential shifts toward more negative values. Once this has occured, the opening of voltage-dependent Ca.sup.++ channels would be counteracted to reduce the influx of Ca.sup.++ ions into the cell because the Ca.sup.++ channels are activated only at a membrane potential above a threshold value. Consequently, drugs having K.sup.+ channel opening activity known as K.sup.+ channel openers can relax vascular smooth muscle and are useful as hypotensive and coronary vasodilating agents.
Pinacidil, chemically N-cyano-N'-(4-pyridyl)-N"-(1,2,2-trimethylpropyl)guanidine monohydrate, is one of known K.sup.+ channel openers. See, U.S. Pat. No. 4,057,636 and I. Ahnfelt-Ronne, J. Cardiovascular Pharmacol., 12, (Suppl. 2): S1-S4 (1988). A number of homologs and analogs of pinacidil were also investigated. See, H. J. Petersen et al., J. Med. Chem., 21, 773 (1978). U.S. Pat. No. 4,567,188 to Niemers et al. discloses a class of 1,1-ethenediamine compounds useful as hypotensive agents.